tbuckley/cabot-search huggingface dataset:
Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, <i>HER2</i>-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial.
Authors: Komal L. Jhaveri, Jonathan W. Goldman, Sara A. Hurvitz, Angel Guerrero-Zotano, Nisha Unni, Adam Brufsky, Haeseong Park, James Ross Waisman, Eddy Shih-Hsin Yang, Iben Spanggaard, Sonya A. Reid, Mark E. Burkard, Aleix Prat, Sherene Loi, John Crown, Ariella Hanker, Cynthia X. Ma, Ron Bose, Lisa DeFazio Eli, Hans Wildiers
Journal: Journal of Clinical Oncology (2022)

1028 Background: N is an oral, irreversible pan-HER TKI with activity against HER2 mutations. Genomic analyses from the SUMMIT MBC cohort following N±F suggest that resistance to N may occur via mutant allele amplification or secondary HER2 mutations. Adding T to N+F in SUMMIT showed encouraging durable responses in patients (pts) with HR+, HER2-mutant MBC and prior CDK4/6 inhibitors (CDK4/6i). Methods: SUMMIT (NCT01953926) enrolled pts with HR+, HER2-negative MBC with activating HER2 mutation(s) and prior CDK4/6i. Pts received N+F+T (oral N 240 mg/d with loperamide prophylaxis, im F 500 mg d1&amp;15 of cycle 1 then q4w, iv T 8 mg/kg initially then 6 mg/kg q3w). During the small, randomized portion of the trial, pts received N+F+T, F+T or F (1:1:1 ratio). Pts randomized to F+T or F could crossover to N+F+T at progression. Efficacy endpoints: investigator-assessed ORR and CBR (RECIST v1.1); DOR; best overall response. Pre-treatment tumor tissue was centrally assessed retrospectively by next-generation sequencing. ctDNA from patient samples was assessed by NGS. Results: SUMMIT has completed enrolment; we report efficacy from 45 pts in the N+F+T cohort, plus 10 pts who progressed on F (n=6) or F+T (n=4) and crossed over to N+F+T (Table). HER2 allelic variants in the 45 N+F+T pts and ORR (%) (pts may have &gt;1 mutation) were: V777L (n=6, 50%), L755S/P (n=15, 40%), S310F (n=4, 50%), exon 20 insertion (n=11, 36%), other KD missense (n=6, 33%), TMD missense (n=2, 0%), exon 19 deletion (n=1, 0%). Conclusions: N+F+T is a promising combination for HR+, HER2-mutated MBC with prior exposure to CDK4/6i, across a range of activating HER2 mutations. Results from the upcoming Apr 2022 data cut, including biomarkers, safety, mechanisms of acquired resistance, and preclinical mechanism of N+T, will be presented. Clinical trial information: NCT01953926. [Table: see text]
Open vs. robot-assisted radical cystectomy with totally intracorporeal urinary diversion: Functional outcomes comparison from a single centre randomised controlled trial
Authors: R. Mastroianni, G. Tuderti, U. Anceschi, A.M. Bove, A. Brassetti, M. Ferriero, L. Misuraca, S. Guaglianone, M. Gallucci, G. Simone
Journal: European Urology (2022)
Toripalimab combined with nab-paclitaxel/gemcitabine as first-line treatment for advanced pancreatic adenocarcinoma: Updated results of a phase Ib/II clinical study.
Authors: Ke Cheng, Wanrui Lv, Xiaofen Li, Chen Chang, Dan Cao
Journal: Journal of Clinical Oncology (2022)

e16244 Background: Much controversy remains regarding the immune-checkpoint-inhibitor plus Nab-paclitaxel/gemcitabine (AG) as the treatment in advanced pancreatic ductal adenocarcinoma (aPDAC). We assess safety and efficacy of toripalimab plus AG in aPDAC, this was the updated results of the study. Methods: This was a phase Ib/II clinical study of toripalimab plus AG as first-line treatment for aPDAC. Toripalimab (240mg, Q3W), combined with AG (nab-paclitaxel 125 mg/m 2 , d1, d8 plus gemcitabine 1000 mg/m 2 , d1, d8) were administrated until the disease progresses/unacceptable toxicity or receiving toripalimab maintenance treatment. The primary endpoints were safety and OS; the secondary endpoints were ORR, DCR and PFS. Predictive biomarkers including gene mutations based on next-generation sequencing and PD-L1 expression were assessed. Results: Until January 2022, 55 chemotherapy-naïve aPDAC evaluable patients (beyond 90% patients with metastatic lesions) to safety and response, ECOG PS≤2 were enrolled. The ORR was 29.1%, the DCR was 90.9%, including 15 patients with PR and 1 patient with CR, 34 patients with SD respectively. 33 patients were alive and 16 patients were still ongoing study. Median PFS was 5.0 months (95% CI: 4.033-5.967), the 6-month PFS rate was 56.4%; median OS was 10.0 months (95% CI: 6.321-13.679), the 1-year OS rate was 69.1%. 2 cases of pseudoprogression were observed. The most frequent treatment related adverse events (TRAE) were anemia (90.1%, G3/4: 9.1%), hypoproteinemia (73%, G3/4: 5.5%), AST elevation (61.0%, G3/4: 3.6%), ALT elevation (60%, G3/4: 5.5%), hypothyroidism (51%, G3/4: 0%), leukocytopenia (45.4%, G3/4: 5.5%), neutropenia (44%, G3/4: 9.1%), nausea (44%, G3/4: 3.6%), rash (38.1%, G3/4: 0%). And 23 patients (41.8%) experienced grade 3/4 TRAE. In the biomarker analysis, all 55 patients were MMR-proficient status; 37 patients were evaluated for PD-L1 expression, PD-L1 positive cases (PD-L1 TPS &gt; 1% and/or CPS &gt; 2, n = 12, 6 patients achieved PR) compared with PD-L1 negative cases (n = 25) presented higher ORR (50% vs 16%). 44 patients were investigated for NGS in 55 evaluable patients, KRAS mutation (86.4%) was the most frequently mutated genes (KRAS G12D = 20 patients, KRAS G12V = 13 patients, KRAS G12R = 4 patients, KRAS G12C = 1 patients), and germline BRCA2 mutation was observed in one patient. The correlation between gene mutation and efficacy and prognosis is under analyzed. Conclusions: The updated results of this phase Ib/II study has met our preset primary endpoint with 69.1% in 1-year OS rate, provided promising evidence that toripalimab in combination with AG has a manageable safety profile and expected antitumor activity. The correlation between biomarkers with clinical efficacy are under investigation. The results supported ongoing combined treatment in aPDAC patients. Clinical trial information: ChiCTR2000032293.
Phase 1b study of weekly split-dose selinexor in soft tissue sarcoma (STS).
Authors: Abdulazeez Salawu, Abha A. Gupta, Esmail Mutahar Al-Ezzi, Sofia Genta, Eoghan Ruadh Malone, Tushar Shailesh Vora, Geoffrey Alan Watson, Olga Vornicova, Lisa Wang, Limore Arones, Madeline J. Phillips, Jasmine Lee, Albiruni Ryan Abdul Razak
Journal: Journal of Clinical Oncology (2022)

11563 Background: Selinexor has demonstrated clinical activity in a variety of tumors including STS. Selinexor dosing at 60mg twice a week or 80mg once a week in later phase trials was associated with gastrointestinal and hematologic toxicities requiring frequent dose interruption and reduction. Preclinical in vivo studies show that selinexor use in a split-dose regimen or sustained-release formula is associated with less toxicity. This phase 1b study aimed to evaluate the safety and tolerability of split-dose selinexor in patients (pts) with advanced STS. Methods: Eligible pts with advanced STS of any histologic subtype, and ECOG performance status (PS) ≤ 1 were treated with split-dose selinexor (40mg, 20mg, 20mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15 and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. Antiemetic prophylaxis (oral dexamethasone and ondansetron) was given to all pts. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAE) by CTCAE v5.0. The secondary endpoint was assessment of quality of life (QoL) using the EORTC QLQ-c30 tool v3. Descriptive analyses of Global Health Status (GHS) QoL scores at screening (baseline) and cycle 2 day 1 (C2D1) were performed. Radiologic tumor assessments (by RECIST v1.1) were performed every 8 weeks while on treatment. Results: Nineteen pts [12 female and 7 male; ECOG 0/1, 8/11; median age 61 years (range 41 – 83)] were enrolled. The most frequent of 12 STS subtypes was leiomyosarcoma (n = 7, 37%). Among 18 patients evaluable for toxicity, there were no grade ≥ 3 TRAE. The most common grade ≤ 2 TRAE were dysgeusia (n = 11, 61%), nausea (n = 11, 61%), fatigue (n = 10, 56%) and vomiting (n = 10, 56%). Grade ≤ 2 hematologic TRAE were thrombocytopenia (n = 6, 33%), neutropenia (n = 4, 22%) and anemia (n = 1, 6%). Dose reduction was required in 3 pts (17%) due to intolerable grade 2 TRAE (fatigue, nausea, thrombocytopenia). No serious adverse event due to selinexor was noted. QoL scores were evaluable for 15 pts. The mean (± SEM) change in GHS QoL score from baseline to C2D1 was -10.6 (± 4.8). Among 16 pts evaluable for radiologic response, the best response was stable disease (SD) in 10 pts (63%), and progressive disease (PD) in 6 pts (37%). Durable clinical benefit (SD for &gt; 16 weeks) was seen in 5 pts (31%; 95%CI 11.0 – 58.7%) The median PFS was 3.6 months (95%CI 1.7 – 7.3). Conclusions: Split-dose selinexor was well tolerated in this heterogeneous group of pts with advanced STS and warrants further interrogation. Updated toxicity, safety, efficacy and QoL data will be presented at the meeting. Clinical trial information: NCT04811196.
THER-02. Pediatric brain tumor cultures reveal differential susceptibility to four oncolytic viruses
Authors: Konstantinos Vazaios, Eftychia Stavrakaki, Lisette Vogelezang, Bernadette van den Hoogen, Rob C Hoeben, Antonio E Chiocca, William F Goins, Esther Hulleman, Trudy Straetemans, Friso G J Calkoen, Jasper van der Lugt, Martine L M Lamfers
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: New therapeutic modalities such as Oncolytic viruses (OVs) are considered possible treatment options for pediatric brain tumors (PBTs) either as monotherapy or as adjuvants to immunotherapies. OVs specifically lyse tumor cells and can induce anti-tumor immune responses. Here, we evaluate the oncolytic potency of different clinically relevant OVs against various PBT entities. METHODS: The effect of four different OVs, Reovirus (R124), Newcastle Disease virus (NDV), Adenovirus (DNX-2401) and Herpes simplex virus-1 (rQNestin 34.5v.1), was assessed on patient-derived cell cultures belonging to four different PBT entities. Cell viability 5 days after virus treatment of diffuse midline gliomas (DMG n=6), atypical teratoid rhabdoid tumors (n=4), glioblastomas (n=1) and ependymomas (n=2) was measured using Cell Titer Glo assay to demonstrate the cytotoxic potency of each virus. RESULTS: Our screenings revealed that DNX-2401, rQNestin and NDV could infect and kill the majority of cell cultures (12 out of 13, 11 out of 13 and 11 out of 13, respectively). rQNestin34.5v.1 required lower amounts of infectious particles per cell (MedianEC50: 0.65±2.7) compared to NDV (3.5±1.7) and DNX-2401 (7.5±14.5), with DMGs being more sensitive for rQNestin34.5v.1 than non-DMGs. R124 was effective in only 6 out of 13 cultures, with DMGs being more resistant with EC50 &amp;gt; 100 (5 out of 6) compared to non-DMG cell lines with EC50 &amp;lt; 8 (5 out of 7). CONCLUSION: All cell lines revealed differential susceptibility to the 4 different OVs with at least one effective OV per cell line. Further analysis of transcriptome and methylome data might uncover genes and pathways which correlate with specific OV susceptibility and provide biomarkers for response prediction. Further investigation is ongoing to interpret how differential susceptibility affects OV-induced anti-tumor immunity.
Low-dose tamoxifen for breast cancer prevention in patients with ductal carcinoma in situ (DCIS) and atypical lesions: A real-world experience.
Authors: Rima Patel, Cao Jin, Amy Tiersten
Journal: Journal of Clinical Oncology (2022)

e12537 Background: Patients diagnosed with non-invasive breast lesions such as DCIS and lobular carcinoma in situ (LCIS) and atypical breast lesions such as atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are at increased risk of developing invasive breast cancer (BC). Tamoxifen 20mg daily for 5 years has shown to be effective for BC prevention in these at-risk patients but its use can be limited by its adverse effects. The recent Tam01 study found that low dose tamoxifen (5mg daily for 3 years) in patients with DCIS, ALH, and ADH resulted in an approximate 50% risk reduction in BC events compared to placebo with a slight increase in hot flashes but no increases in uterine cancer or venous thromboembolism within the tamoxifen group (PMID: 30973790). The objective of this study was to evaluate the use of low dose tamoxifen at our institution and determine how many patients preferred this option. Methods: We performed a retrospective chart review of women who were diagnosed with DCIS, LCIS, ADH, and/or ALH at our institution from January 2019 to December 2021 and subsequently started adjuvant tamoxifen. Patients with history of invasive BC were excluded. Patients were categorized as being on standard dose (20mg daily) or low dose (5mg daily or 10mg every other day) tamoxifen. Fisher’s exact test was used to compare rates of standard and low dose tamoxifen use in the entire cohort as well as in pathology-based subgroups. Results: We included 130 women diagnosed with DCIS, LCIS, ADH and/or ALH and who started adjuvant tamoxifen. The median age at diagnosis was 50 years and 68% were premenopausal. Overall, 62% (n = 80) of women started standard dose tamoxifen and 38% (n = 50) low dose tamoxifen. Among 63 patients who were offered both standard and low dose options, 76% (n = 48) initiated low dose tamoxifen (p &lt; 0.0001). Twenty women were noted to be hesitant to start standard dose tamoxifen due to concern for side effects or preexisting menopausal symptoms but were agreeable to the low dose option. Of the 86 patients with DCIS, a preference for standard dose tamoxifen was observed (74% vs 26%, p = 0.0016). Among 44 patients with LCIS, ADH, and/or ALH, more patients were on low dose tamoxifen (64% vs 36%, p = 0.282). Nine percent (n = 7) of patients on standard dose tamoxifen switched to low dose due to adverse effects including hot flashes, mood changes, and insomnia. Conclusions: At our institution, in patients offered both low dose and standard dose tamoxifen, more than 75% started low dose tamoxifen. The low dose option was more frequently used for atypical lesions such as ADH, ALH and LCIS. In women at higher risk of invasive BC who may be reluctant to start standard dose tamoxifen or intolerant of it, low dose tamoxifen should be considered and offered.
A deep-learning system predicts glaucoma incidence and progression using retinal photographs
Authors: Fei Li, Yuandong Su, Fengbin Lin, Zhihuan Li, Yunhe Song, Sheng Nie, Jie Xu, Linjiang Chen, Shiyan Chen, Hao Li, Kanmin Xue, Huixin Che, Zhengui Chen, Bin Yang, Huiying Zhang, Ming Ge, Weihui Zhong, Chunman Yang, Lina Chen, Fanyin Wang, Yunqin Jia, Wanlin Li, Yuqing Wu, Yingjie Li, Yuanxu Gao, Yong Zhou, Kang Zhang, Xiulan Zhang
Journal: Journal of Clinical Investigation (2022)

BackgroundDeep learning has been widely used for glaucoma diagnosis. However, there is no clinically validated algorithm for glaucoma incidence and progression prediction. This study aims to develop a clinically feasible deep-learning system for predicting and stratifying the risk of glaucoma onset and progression based on color fundus photographs (CFPs), with clinical validation of performance in external population cohorts.MethodsWe established data sets of CFPs and visual fields collected from longitudinal cohorts. The mean follow-up duration was 3 to 5 years across the data sets. Artificial intelligence (AI) models were developed to predict future glaucoma incidence and progression based on the CFPs of 17,497 eyes in 9346 patients. The area under the receiver operating characteristic (AUROC) curve, sensitivity, and specificity of the AI models were calculated with reference to the labels provided by experienced ophthalmologists. Incidence and progression of glaucoma were determined based on longitudinal CFP images or visual fields, respectively.ResultsThe AI model to predict glaucoma incidence achieved an AUROC of 0.90 (0.81-0.99) in the validation set and demonstrated good generalizability, with AUROCs of 0.89 (0.83-0.95) and 0.88 (0.79-0.97) in external test sets 1 and 2, respectively. The AI model to predict glaucoma progression achieved an AUROC of 0.91 (0.88-0.94) in the validation set, and also demonstrated outstanding predictive performance with AUROCs of 0.87 (0.81-0.92) and 0.88 (0.83-0.94) in external test sets 1 and 2, respectively.ConclusionOur study demonstrates the feasibility of deep-learning algorithms in the early detection and prediction of glaucoma progression.FUNDINGNational Natural Science Foundation of China (NSFC); the High-level Hospital Construction Project, Zhongshan Ophthalmic Center, Sun Yat-sen University; the Science and Technology Program of Guangzhou, China (2021), the Science and Technology Development Fund (FDCT) of Macau, and FDCT-NSFC.
Synthesis of multi-branched Au nanocomposites with distinct plasmon resonance in NIR-II window and controlled CRISPR-Cas9 delivery for synergistic gene-photothermal therapy
Authors: Weiwei Tao, Xiaolan Cheng, Dongdong Sun, Yang Guo, Neng Wang, Jie Ruan, Yue Hu, Min Zhao, Tong Zhao, Hui Feng, Lu Fan, Cai Lu, Yong Ma, Jinao Duan, Ming Zhao
Journal: Biomaterials (2022)
When I use a word . . . . Counterfactual medical history: the death of Charles II
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

A counterfactual statement, originally a philosophical concept, expresses an assessment of what might have happened if certain unfulfilled conditions had actually occurred. The life of King Charles II offers more than one opportunity for counterfactual speculation. The King fell ill on Monday 2 February 1685 and died on the following Friday. Of the many speculated causes of his death, the most parsimonious is that gout led to renal insufficiency, and the consequent uraemia caused convulsions, a major feature of his illness. Iatrogenic dehydration, secondary to bleeding and cupping, scarifying, blistering and clystering, and the administration of purgative and emetic medicines, would have caused acute renal insufficiency and further deterioration. Counterfactually, if modern treatments had been available, the King’s illness could have been prevented or delayed and his life could have been prolonged. Because his wife Queen Catherine failed to give him an heir, his brother, the Duke of York assumed the throne as James II in 1685, but was deposed in the Glorious Revolution of 1688–9 by William III. Had modern medicine been available and an heir emerged, the House of Orange might never have become established in Britain.
Trial in progress: A phase 1-2, first-in-human, open label, dose escalation and expansion study of AU-007, a monoclonal antibody that binds to IL-2 and inhibits IL-2Rα binding, in patients with advanced solid tumors.
Authors: James Robert Vasselli, Sophia Frentzas, Andrew James Weickhardt, Paul L. de Souza, Jenny Tang, Tim Wyant, Inbar Amit, Yanay Ofran, Aron Knickerbocker
Journal: Journal of Clinical Oncology (2022)

TPS2671 Background: AU-007 is a computationally designed, monoclonal antibody that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to high affinity trimeric IL-2 receptors (IL-2R) consisting of CD25, CD122, and CD132 expressed on Tregs and vascular endothelium, but its binding to low affinity dimeric IL-2Rs (CD122 and CD132) expressed on T effector and NK cells is unhindered. Thus, AU-007 redirects endogenously produced or exogenous IL-2 (aldesleukin) towards activation of immune stimulating T effector and NK cells, while diminishing Treg activation and expansion. AU-007 will also bind and redirect newly secreted endogenous IL-2 resulting from A/IL-2 driven T cell expansion in the tumor, converting a Treg mediated autoinhibitory loop into an immune stimulating loop. AU-007 is unique in the IL-2 therapeutic field as engineered exogenous, recombinant “non-CD25” IL-2s in development cannot address the autoinhibitory effect of endogenous IL-2. Preclinically, AU-007 has been demonstrated to capture endogenous human IL-2 in vivo. AU-007 with a single low dose of IL-2 has demonstrated efficacy in multiple cancer models and has an excellent safety profile in non-human primates. Methods: This first-in-human, multicenter, open label Phase 1- 2 study evaluates the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors (CT-2021-CTN-03938-1). Phase 1 consists of 3 escalation arms each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). Patients with melanoma, renal cell carcinoma (RCC) and 17 selected solid tumors are eligible. Prior treatment with check point inhibitors is allowed. In Arm A, escalating doses of Q2w AU-007 are evaluated in sequential escalation cohorts. In Arm B, a single dose of aldesleukin is given with the initial AU-007 dose. AU-007 is given at a fixed dose Q2w with an escalating single aldesleukin dose in sequential escalation cohorts. In Arm C, AU-007 is evaluated in combination with aldesleukin, both given Q2w. AU-007 is administered at a fixed dose with an escalating dose of aldesleukin in sequential cohorts. The Phase 2 cohort expansion portion of the study evaluates the initial efficacy at the RP2D defined in escalation cohorts A, B, and C in 3 matching expansion cohorts of up to 20 patients each. Patients with advanced melanoma, RCC and other tumors including, but not limited to, Merkel Cell Carcinoma, NSCLC, and urothelial cancer are eligible. Enrolment to the study commences in Australia, with US sites planned to open later in 2022. Clinical trial information: CT-2021-CTN-03938-1.
Clinical and epidemiological features of penile squamous cell carcinoma according to pathological nodal stage in a Brazilian cancer reference hospital.
Authors: Daniel D Almeida Preto, Bruno Lordelo, Rosielly Melo Tavares, Nathália Gimenes Afonso, Hadson Silva Araujo, Joao Neif, Luis Eduardo Rosa Zucca, Flavio Mavignier Carcano
Journal: Journal of Clinical Oncology (2022)

e17017 Background: Penile cancer is a rare disease worldwide, but in the developing countries represent 2% of male cancers, and sociocultural issues are closely related to risk. Lymph node status is a key prognostic factor, and almost 60% of patients has lymph node disease at diagnosis. Perioperative treatment for patients with regional lymph node disease is essential for a better outcome. Methods: We retrospectively reviewed all penile cancer patients, with histological confirmation, between 2009 and 2019 at Barretos Cancer Hospital (Brazil). Only squamous cell carcinoma that performed lymphadenectomy were included. Univariable analysis were performed to explore association between clinical and pathological features. Cumulative survival probabilities were calculated using the Kaplan-Meier method and differences between survivals were tested using the log-rank test. Results: One hundred and thirteen patients were eligible for analyses. The mean age was 55.7 year. Most of the patients were declared white, in a stable relationship and had a lower education level, with more than 70% of patients attending only elementary school. Clinical-pathological staging concordance was 43%. Overall survival was related to pathologic lymph node staging (pN), ranging from 111 months for pN0 individuals to 46.9 months for pN3 (p &lt; .001). Considering only pN2-3 stages, only 54% of patients were submitted to adjuvant treatment and those had significantly improved 5 years cumulative survival, almost 50% versus 20% (p = .027). Only one patient was submitted to neoadjuvant therapy. Conclusions: The epidemiological profile matches with the current literature, reaffirming this public health issue in low-income countries. Accurated lymph node staging is essential to define the prognosis and an agressive multi-modality approach could improve results in the perioperative nodal metastatatic setting. Further prospective controlled studies should be stimulated in this context.